Induction Of Cyclooxygenase-1 And-2 Modulates Angiogenic Responses To Engagement Of Alpha(V)Beta(3)

Prostaglandins and cyclooxygenase (COX) have been implicated in the angiogenesis that occurs around tumours, but how they are induced is unclear. Prostaglandin formation is regulated by the availability of arachidonic acid and/or COX activity that in turn are controlled by activation of G-protein-coupled receptors or kinase receptors. Adhesion receptors provide another potential level of control as they transduce a variety of 'outside-in' signals implicated in inflammation. We examined whether engagement of the vitronectin receptor (alpha(v) beta(3) ) modulated prostacyclin (PGI(2) ) formation in human umbilical vein endothelial cells (EC). Engagement of EC alpha(v) beta(3) by vitronectin (versus fibronectin or gelatin) or by monoclonal antibodies (mAbs) LM609 and LIBS6, enhanced PGI(2) generation and also induced expression of both COX-1 and -2 isoforms. alpha(v) beta(3) engagement also led to vascular endothelial cell growth factor (VEGF) generation and EC proliferation that was attenuated by inhibition of both COX-1 and COX-2. COX-1 inhibition also prevented new vessel formation in an in vitro model of angiogenesis that is alpha(v) beta(3) dependent. Inhibition of angiogenesis by the COX-1 inhibitor was partially reversed by removal of the inhibitor or by addition of the stable analogue of PGI(2) , iloprost. These findings strongly indicate that alpha(v) beta(3) -mediated angiogenesis is partly due to induction of both isoforms of COX.